ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following a traumatic brain injury (TBI), and substantial evidence suggests therapies targeting the interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation. Despite the promise, there have been limited attempts to move anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lack of progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1 signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injury mechanisms and injury severities, and that it is necessary to understand the secondary injury mechanism as they relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead to neurodegeneration, a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction, and is a known risk factor for the development of Alzheimer?s disease and related dementias. The current knowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury. Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling, and our model of mild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge by testing the role of IL-1R1 following a mild TBI, and for the first time, define a cellular mechanism for the pathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered a critical role for the brain endothelium in regulating neuroinflammation, which is dependent on IL-1R1. Our preliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following a mild TBI is driven by neuroinflammation and vascular dysfunction, which can be reduced through suppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement of endothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mild TBI, and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our results will fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotection after a mild TBI, and potential for other disease associated with neuroinflammation (i.e., Alzheimer?s disease).